Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. The highest incidence of disease occurs at the extremes of age. The elderly are at high risk of pneumococcal infection, have an increased incidence of accompanying bacteremia and a higher mortality rate compared to younger adults. It is projected that between 2000 and 2040, the number of Americans ?65 years of age will more than double. The rapid growth of the aging population has resulted in a significant increase in elderly individuals with end-stage renal disease (ESRD). Moreover, older (>65 yrs) individuals are the fastest growing population requiring renal replacement therapy. Streptococcus pneumoniae is the most common bacterial pathogen and the incidence of invasive pneumococcal disease (IPD) is 12x higher in renal transplant (RT) and dialysis recipients. It is recommended that both elderly>65 and RT/dialysis recipients be vaccinated with a combination of the 13- valent pneumococcal conjugate vaccine followed by the 23-valent pneumococcal polysaccharide vaccine. Previous studies have demonstrated suboptimal vaccine responses in both RT and dialysis populations and failed to elucidate the possible foundation of the disappointing immune responses to the PCV regimens. Our preliminary studies suggest that IgM memory B cells and expression of tumor necrosis family receptors TACI and BAFF-R, both crucial in the immune response to polysaccharide antigens, are deficient in the RT recipients. We hypothesize that poor responses to pneumococcal vaccines in aging dialysis and RT populations are in part related to an altered inflammatory environment and in part related to B cell perturbations, specifically in memory B cell numbers and in TNFR expression. We will test this hypothesis by first measuring antibody responses and B cell numbers and phenotype to pneumococcal vaccination in RT and dialysis recipients >65 years of age and compare these groups to healthy age-matched and young persons. In addition, we hypothesize that elderly RT/dialysis recipients have a unique combination of inflammatory markers and intrinsic B cell defects, or profile, and that this profile dictates vaccine responses. To this purpose, Investigate the underlying mechanisms of altered B cell responses in the aging RT and dialysis populations by elucidating inflammatory environment, B cell functionality and B cell surface receptor and gene expression using single cell quantitative PCR, specifically focused on the TNF superfamily. Finally, we will study the effect of PCV/PPV vaccination on markers predicting graft rejection to ensure vaccine safety. We postulate that CpG-ODN may be a useful adjuvant to restore full expression of TACI, however in the RT population this may be an inappropriate adjuvant. We will therefore define the effects of CpG-ODN and BAFF on expression of TNFR and tolerance associated genes. This work is important and novel because it examines antigen-specific responses post-immunization to the number one cause of pneumonia in the rapidly growing elderly RT recipients. The study will correlate functional responses with inflammatory status, B cell fitness and surface expressed molecules potentially providing information for more efficacious and safe pneumococcal vaccination strategies. Studies designed to explore the underlying causes of poor vaccine responsiveness in the aging dialysis and RT recipient populations that may potentially lead to improved vaccine formulations are vital to the VA healthcare mission.